C-X-C Chemokine Receptor Inhibitors–The Emerging Therapeutic Agents

C-X-C chemokine receptors (CXCR) is a family of G protein-coupled receptors that comprises of a large subfamily of the rhodopsin superfamily of 7-transmembrane domain receptors. Two types of chemokine receptors have been identified including monogamous chemokine receptors (bind to only one specific chemokine) and promiscuous chemokine receptors (bind to more than a dozen chemokines). A total of seven C-X-C chemokine receptors are known from CXCR1 through to CXCR7 out of which CXCR 1, 2 and 4 inhibitors being the key CXCR inhibitors are being developed as potential drugs.

The CXCR1 and 2 mediates the GPCR signaling pathways and cellular functions such as calcium release, activation of Ras/MAPK, PI3K signaling cascades as well as receptor internalization and chemotaxis. CXCR4 antagonist blocks the binding of its cognate ligand, stromal cell-derived factor 1 (SDF-1).

The CXCR inhibitors mainly target oncology based indications including acute myeloid leukemia, multiple myeloma, hematological malignancies, advanced solid tumors, and glioblastomamultiforme. Although chemokines and their receptors were originally identified as mediators of inflammatory diseases, however, it is being increasingly recognized that they serve as bridges between tumor cells and stromal cells. They also target respiratory, cardiovascular, metabolic, infectious and immune diseases.

Currently, there is only one FDA approved CXCR inhibitor (type 4), Mozobil (plerixafor) which received marketing approval in 2008 for Non-Hodgkin’s Lymphoma and Multiple Myeloma. The pipeline activity in this area is robust with 20+ active pipeline products. Various companies including BioLineRx, DompéFarmaceutici, and X4 Pharmaceuticals are developing therapeutic candidates in the late clinical stage (Phase III). Thus, the CXCR inhibitors development has emerged as a potential area of therapeutic research.